Immunogenetics seminars

Highly pathogenic avian influenza and porcine reproductive and respiratory syndrome impose major disease and economic burdens on poultry and swine production. Paula Chen and Kiho Lee examine gene editing as a way to reduce susceptibility and improve animal health. Chen presents genome-editing approaches to preventing poultry disease; Lee discusses improving the genetic value of pigs through gene-editing technology. The programme connects these strategies to the continuing challenges posed by viral outbreaks, evolving PRRS variants and debate about vaccination as a control measure.

Laura Graus explains a multi-omics workflow that combines B-cell receptor repertoire analysis with phenotypic profiling using dCODE Klickmer technology. The seminar examines how the pipeline characterizes B-cell responses after vaccination and infection, including the function and dynamics of memory B-cell reactivation. Its application to vaccination studies illustrates how single-cell measurements can inform HIV-1 vaccine design.

Shimon Sakaguchi, Mary E. Brunkow and Fred Ramsdell explain how peripheral immune tolerance prevents the immune system from attacking the body. Sakaguchi follows the identification of regulatory T cells, the CD25 marker, and the relationship between central tolerance and active suppression of self-reactive cells. He considers how changing regulatory T-cell activity could support cancer treatment and transplantation. Brunkow describes genetic investigation of scurfy mice, identification of FOXP3, and the connection between mutations in this gene and human IPEX syndrome. The work establishes a molecular basis for the development and function of regulatory T cells. Ramsdell traces the move from these basic discoveries toward therapeutic strategies, including engineering a patient’s regulatory T cells to target inflammation in rheumatoid arthritis. He discusses early clinical investigation and the ambition of restoring immune balance; these approaches are presented as developing treatments rather than established cures.

Stephen Quake examines antibody repertoires as populations shaped by diversification and selection. Recombination, junctional changes and mutation create many potential antibodies, but their realised diversity and similarity between individuals remain important questions. High-throughput sequencing in humans and model organisms is used to study these patterns and evolutionary convergence.

In this lecture, Dr Stevens will discuss recent work that implicates brain immune cells, called microglia, in sculpting of synaptic connections during development and their relevance to autism, schizophrenia and other brain disorders. Her recent work revealed a key role for microglia and a group of immune related molecules called complement in normal developmental synaptic pruning, a normal process required to establish precise brain wiring. Emerging evidence suggests aberrant regulation of this pruning pathway may contribute to synaptic and cognitive dysfunction in a host of brain disorders, including schizophrenia. Recent research has revealed that a person’s risk of schizophrenia is increased if they inherit specific variants in complement C4, gene plays a well-known role in the immune system but also helps sculpt developing synapses in the mouse visual system (Sekar et al., 2016). Together these findings may help explain known features of schizophrenia, including reduced numbers of synapses in key cortical regions and an adolescent age of onset that corresponds with developmentally timed waves of synaptic pruning in these regions. Stevens will discuss this and ongoing work to understand the mechanisms by which complement and microglia prune specific synapses in the brain. A deeper understanding of how these immune mechanisms mediate synaptic pruning may provide novel insight into how to protect synapses in autism and other brain disorders, including Alzheimer’s and Huntington’s Disease.

Fred Ramsdell traces the discovery of FOXP3 from the striking immune phenotype of the scurfy mouse to the mapping and cloning of the responsible gene. He explains how linking a disease phenotype to its genetic cause opened a route to understanding the regulation of immune responses and the biology of regulatory T cells. The lecture considers FOXP3 as a regulator of immune function and the implications of this history for therapeutic intervention. It argues for the continuing value of phenotype-first research and naturally occurring disease mutations in discovering biological mechanisms and identifying potential treatment targets, even as genome sequencing becomes increasingly routine.

Alexander Rudensky examines why an immune system capable of amplifying responses to pathogens also needs a dedicated mechanism of restraint. He connects the activity of effector CD4 T cells to the emergence of regulatory T cells and explores how loss of this regulatory population accounts for the severe disease associated with FOXP3 deficiency. The lecture follows genetic experiments that test the continuing requirement for regulatory T cells and trace the stability of their lineage. It also considers regulatory T cells generated outside the thymus, their relationship with commensal microorganisms, and their role in limiting inflammation at mucosal barriers. Together these studies explain how a specialised cell lineage can maintain immune tolerance throughout life.

Shimon Sakaguchi explains how regulatory T cells restrain immune responses and maintain tolerance to the body’s own tissues. He follows experimental evidence linking the removal of particular CD4 T-cell populations to autoimmune disease and the restoration of regulation to protection against excessive immune activity. The lecture connects these mouse experiments with human immune dysregulation, including IPEX, and with the role of FOXP3 in regulatory T-cell biology. It develops the idea that active cellular suppression is a continuing requirement for immune balance, with implications for understanding autoimmunity and for manipulating immune responses therapeutically.